With a share of approximately 27% having value of S860-billion dollar, injectables were No. 2 in the drug delivery market in 2010, preceded only by oral medication. Double-digit growth rates, mainly triggered by biotech-derived products and the rise of injectable generics show that the importance of this segment is still on the rise. Still, prefillable glass syringes and vials are the most common primary packaging containers for modern injectables. Various glass container systems are traditionally used for the storage of parenterals. However, the container of a product intended for parenteral use has to ensure that functionality and drug delivery accuracy and always comply with the specifications throughout the product shelf life. Several factors have to be considered when choosing the right packaging/container for an injectable product, such as drug product formulation properties, dosage, type of application, stability, storage condition and duration, and end-user friendliness. It may be necessary to develop different packaging systems for one product to satisfy different patient group needs.
A dominant trend in primary packaging is the evolution from simple bulk packaging materials toward ready-to-sterilize (RTS) or ready-to-use (RTU) primary packaging components and systems. Further, the Regulatory authorities all over the world are paying greater attention to the use of appropriate primary packaging materials with the consequence that standards have become very comprehensive and detailed. Quality requirements for glass containers, which are likely to be tightened up, include specifications regarding the particle load, lower rates of cracks or cosmetic defects, and smaller dimensional tolerances. Available container closure systems/devices include vials, reconstitution kits, disposable or prefillable syringes, ampoules and auto injectors or pen systems. Although plastic materials are also being considered for use as primarily packing materials particularly for infusions for parenteral use; the challenge has been to develop packaging which are compatible with the contents, minimizes extractables/leachables, are solvent-resistant, and durable.
Racemic 4-[1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole, which is known under the name medetomidine, is a selective and potent α2-adrenoceptor agonist. Medetomidine has been used as an antihypertensive agent and as a sedative-analgesic agent. It has further been observed that this compound also possesses anxiolytic effects and can therefore be used in the treatment of general anxiety, panic disorder and various types of withdrawal symptoms.
The d-enantiomer of medetomidine, the generic name of which is dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an α2-adrenoceptor agonist for general sedation/analgesia and the treatment of hypertension or anxiety. U.S. Pat. Nos. 5,344,840 and 5,091,402 discuss dexmedetomidine in perioperative and epidural use, respectively. For example, when used in perioperative care, dexmedetomidine can reduce the amount of anesthetic necessary to anesthetize a patient. Additionally, U.S. Pat. No. 5,304,569 discusses the use of dexmedetomidine in treating glaucoma, and U.S. Pat. No. 5,712,301 discusses the use of dexmedetomidine for preventing neurodegeneration caused by ethanol consumption. Furthermore, U.S. Pat. No. 6,716,867 discloses methods of sedating a patient while in an intensive care unit by administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the patient.
Precedex™ (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Precedex (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic ready-to-use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole monohydrochloride.
Precedex™ in 0.9% Sodium Chloride Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 8.0. Precedex™ (dexmedetomidine hydrochloride in 0.9% Sodium Chloride) injection is available as 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL) in 20 mL clear glass vials, 50 mL and 100 mL clear glass bottles, respectively. Containers are intended for single use only. Each ml contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg sodium chloride in water. The solution is preservative-free and contains no additives or chemical stabilizers.
Precedex™ is indicated for sedating initially intubated and mechanically ventilated patients during treatment in an intensive care setting and for sedation of non-intubated patients prior to and/or during surgical and other procedures. Precedex™ should be administered by continuous infusion not to exceed 24 hours. Precedex™ has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation.
Patients in intensive care unit (ICU) are treated with many interventions most notably endotracheal intubation and mechanical ventilation that are observed to be distressing. Pain is the most common in intensive care unit (ICU) patients. Sedation is commonly used in the intensive care unit (ICU) to reduce patient discomfort, improve tolerance with mechanical ventilation and reduce metabolic demands during respiratory and hemodynamic instability. Continuous and deep sedation have been associated with increased risk of delirium, longer duration of mechanical ventilation, increased length of ICU and hospital stays, and long-term risk of neurocognitive impairment, post-traumatic stress disorder, and mortality. Sedation interruption and protocolized sedation have been associated with decreased length of ICU stay and reduced duration of mechanical ventilation.
Sedation has been achieved with clonidine, midazolam or propofol in intensive care units (ICUs). Dexmedetomidine is a more potent a-agonist; it is showing promise as a sedative agent in ICU and in pediatric anesthesia due to its shorter elimination half-life. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. Use of dexmedetomidine may have an advantage in maintaining lighter levels of sedation during early sedation, which is associated with improved clinical outcomes.
U.S. Pat. Nos. 8,242,158; 8,338,470; 8,436,033; 8,455,527 and 8,648,106 disclose ready-to-use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 4 μg/mL disposed within a sealed glass container.
U.S. Pat. No. 8,242,158 provides a ready-to-use liquid pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 4 μg/mL disposed within a sealed glass container. U.S. Pat. No. 8,242,158 also discloses studies for selection of packaging components for premixed dexmedetomidine pharmaceutical composition. In order to identify suitable primary packaging components for the 4 μg/mL premixed dexmedetomidine composition in 0.9% NaCl, stability studies were conducted in various configurations including glass vials, ampoules, plastic flexible containers (CR3 elastomer copolyester ether containers (Hospira, Inc., Lake Forest, Ill.), PVC and VisIV™ plastic containers (Hospira, Inc., Lake Forest, Ill.)), and Ansyr® syringes (Hospira, Inc., Lake Forest, Ill.). The samples of 4 μg/mL premixed dexmedetomidine composition in 0.9% NaCl, with pH of 4.7-6.2, were packed in aforementioned packs and autoclaved. The stability of the autoclaved samples were tested under accelerated conditions (40° C./75% RH) and evaluated over a period of 5 months. After five months under accelerated conditions the potency of the premixed dexmedetomidine composition in glass ampoules and vials remained at about 98% while that in the syringe was found to be about 90%. In PVC and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.), after the initial potency loss to around 80% no further loss of potency was observed during the five month period. The cause of potency loss in PVC bags and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) during autoclaving was investigated. Related substances testing on autoclaved premixed dexmedetomidine composition filled in PVC and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.) revealed that potency drop did not occur due to degradation, because the total percent of impurities was much less than 20%. Loss of potency may be due to either adsorption (restricted to the surface of the flex bag) and/or absorption (not restricted to the surface) of the drug in to the flex bags. To confirm the absorption/adsorption phenomena, the CR3 elastomer copolyester ether bags and PVC bags that showed 20% potency loss were emptied and rinsed with methanol. The rinse solvent was tested for dexmedetomidine. Nearly all the drug was recovered from CR3 elastomer copolyester ether bags indicating adsorption and only 1% of the drug was recovered from PVC bags indicating absorption.
The related substances results indicated that premixed dexmedetomidine composition in VisIV™ plastic bags (Hospira, Inc., Lake Forest, Ill.) had high impurity levels higher than levels observed in ampoules, vials, syringes, PVC bags and CR3 elastomer copolyester ether bags (Hospira, Inc., Lake Forest, Ill.).
U.S. Pat. Nos. 8,324,260; 8,507,542; US 2013/0096170; US 2013/0096172 and US 2014/0005243 disclose method of sedation or analgesia in a pediatric patient in need thereof, wherein the method comprises administering dexmedetomidine to the pediatric patient; wherein the dexmedetomidine is administered as a first loading dose at a concentration of about 0.005 to about 0.25 μg/kg prior to a second maintenance dose at a concentration of about 0.005 to about 0.2 μg/kg/hr; wherein the pediatric patient is about one month to about 17 years of age; and wherein the dexmedetomidine is administered as a continuous infusion for a time period of less than about 36 hours.
The aforementioned prior art disclose that all types of Non-Glass containers like PVC bags, CR3 elastomer copolyester ether bags and ADDVantage® PVC bags, are not suitable for premix compositions of dexmedetomidine composition due to loss of drug potency either by adsorption and/or absorption phenomena.
Anderson et al., (Am J health-Syst Pharm—Vol 69, Apr. 1, 2012) discloses that the dexmedetomidine diluted to 4 mg/mL in 0.9% sodium chloride injection was stable for only 48 hours at 20-25° C. and 14 days at 5° C. when stored in polypropylene (PP) syringes. The samples of diluted dexmedetomidine stored in syringes at room temperature exhibited a loss of drug concentration of <10% over 48 hours; the refrigerated samples exhibited a loss of drug concentration of <5% over 14 days. The assay results of Anderson et al in PP syringe conclude that premix compositions of dexmedetomidine were susceptible to loss of drug potency of about 5% over 48 hours. Therefore, Polypropylene was not considered to be an appropriate Material of Construction (MOC) to be suitable as multilayered plastic bags for packing premix compositions of dexmedetomidine.
U.S. Pat. Nos. 9,649,296 and 9,717,796 disclose a premixed ready-to-use for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.5 μg/mL to about 20 μg/mL and a sugar disposed in a flexible plastic container substantially free of DEHP.
Further, the use of glass containers for administering premix compositions particularly as infusion are highly troublesome and dangerous due to the brittle nature of glass and its tendency to break, which renders it highly unsafe particularly for use in intensive care unit (ICU) patients.
Thus the present invention can be said to solve the long felt need for containers/packaging for premixed compositions for parenteral use which are user-friendly, safe, flexible, easy to transport and store, compatible with the contents, minimizes extractables/leachables, solvent-resistant, and durable. The present invention alleviates the limitations in the art by providing such containers/packaging for injectable preparations.